The hallmark of Alzheimer's disease (AD) is the presence of senile plaques in the brain, which are composed of a central deposition of β-amyloid peptide. Deposits of β-amyloid peptide play an important role in the pathogenesis of AD as shown by genetic, neuropathological, and biochemical evidence. β-Amyloid (Aβ) peptide is a 39-43 amino acid peptide derived from the amyloid precursor protein (APP) by proteolytic processing. Both Aβ1-40 and Aβ1-42 are components of the deposits of amyloid fibrils found in brain tissue of AD patients. The aggregation of monomeric Aβ peptides into toxic fibrils and plaques has a rate-limiting nucleation phase followed by rapid extension. Aβ1-42 is believed to play a more important role in the early nucleation stage, thus being more “amyloidogenic” than Aβ1-40.
Short peptides and small molecules can influence the structure and aggregation of Aβ, and these are effective neuroprotective agents. Peptides that are partially homologous to the central hydrophobic region of Aβ (residues 17-21), but that contain amino acids that prevent the adoption of Aβ-sheet structure bind to Aβ and inhibit amyloid formation invitro and disaggregate preformed Aβ fibrils. One such analog is the LPFFD peptide that has significant effects on the higher-order structure of Aβ in a shorter time domain than that in which the β-sheet-breaking effect appears, and this has implications for their protective effect. Another such peptide is the analog of the GxxxG motif of the Aβ at residues 25-29. Approaches have targeted Aβ utilizing peptides based on the GxFxGxF scaffold expected to interact with the C terminus of Aβ. The most active compound RGTWEGKW was shown to inhibit fibril formation and reduce cellular toxicity. The Alternating hydrophilic-hydrophobic nature of this peptide may help to disrupt Aβ aggregation.
The mechanism by which natural protein ligands interact with Aβ and reduce its toxicity in the cellular environment is still not clearly understood. Numerous experiments have been conducted to determine possible natural protein binding partners of Aβ. Some of these natural ligands may be a missing link between Aβ accumulation and cellular toxicity.
What is needed are improved compositions for the delivery of peptide ligands that interact with Aβ and can reduce its toxicity in the cellular environment.